We propose to synthesize potent, enzyme-resistant and receptor- specific opioid peptide analogs. The development of both agonists and antagonists with high specificity for the three major opioid receptor types (mu, delta, kappa) will be attempted. The analog design will primarily be based on the principle of conformational restriction through peptide cyclizations via side-chains. The compounds to be synthesized will serve a dual purpose: a) they will represent novel tools for research aimed at elucidating the molecular mechanism(s) of action of opioid compounds and at clarifying the physiological role of the various opioid receptor classes; and b) some of the peptide analogs might have potential as novel analgesics. To reach these goals we use an interdisciplinary approach based on the well-integrated application of chemical, physico-chemical, biochemical and pharmacologic methods. Specific aims include: a) synthesis of cyclic opioid peptide analogs structurally related to dermorphin and beta- casomorphin (Phe in 3-position); b) preparation of cyclic peptides related to enkephalin and metorphamide (Phe in 4-position); c) synthesis of stable dynorphin A-(1-13) analogs characterized by various peptide bond replacements in the 1-2 position and/or containing cyclic elements in the middle or C-terminal regions of the peptide chain; d) conformational studies by NMR spectroscopy and X-ray diffraction analysis; e) determination of receptor affinities and selectivities of the new compounds in binding assays based on displacement of mu-, delta- and kappa-selective radioligands from rat brain or guinea pig ileum membrane binding sites; f) evaluation of agonist or antagonist properties of the analogs in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum and of the vasa deferentia of the mouse, rat and rabbit; g) examination of the stability of the compounds against enzymatic degradation; and h) tests of the analgesic properties of the analogs in vivo using the mouse or rat tail flick test.